Journal
MOLECULAR METABOLISM
Volume 59, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.molmet.2022.101458
Keywords
Intestine; O-GlcNAcylation; SGLT1; Glucose absorption; GLP-1
Categories
Funding
- Japan Society for the Promotion of Science [18H02862, 19K08998]
- Shiga University of Medical Science
- Nipro
- Bayer Yakuhin
- Boehringer-Ingelheim
- Kyowa Hakko Kirin
- Kowa Pharmaceuticals
- Sumitomo Dainippon Pharma Co., Ltd.
- DaiichiSankyo
- Takeda Pharmaceutical Company Limited
- Novo Nordisk Pharma
- Mitsubishi Tanabe
- Sanwa Kagaku Kenkyusho
- MSD
- Mochida Pharmaceutical Co., Ltd.
- Grants-in-Aid for Scientific Research [19K08998, 18H02862] Funding Source: KAKEN
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Loss of O-GlcNAcylation in the intestine reduces glucose absorption by suppressing SGLT1 expression. This study provides new insights into the role of O-GlcNAcylation in glucose metabolism and suggests potential treatments for malabsorption, obesity, and diabetes.
Objective: The intestine is an important organ for nutrient metabolism via absorption and endocrine systems. Nutrients regulate O-GlcNAcy-lation, a post-translational modification of various proteins by O-GlcNAc transferase (OGT). We have previously shown that general OGT knockout induced severe weight loss and hypoglycaemia in mice, but little is known about how O-GlcNAcylation in the intestine modulates nutrient metabolism, especially glucose metabolism, through absorption. We aimed to reveal the roles of O-GlcNAcylation in glucose absorption by the small intestine and elucidate the mechanism by which O-GlcNAcylation regulates sodium-glucose cotransporter 1 (SGLT1) expression.& nbsp;Methods: First, we fasted normal mice and examined the changes in glucose transporters and O-GlcNAcylation in the intestine. Then, we generated two lines of small intestine-specific OGT-deficient mice (congenital: Ogt-VKO, tamoxifen-inducible: Ogt-iVKO) and observed the changes in body weight and in glucose and lipid metabolism. Finally, we investigated Sglt1 gene regulation by O-GlcNAcylation using enter-oendocrine STC-1 cells.& nbsp;Results: Fasting decreased O-GlcNAcylation in the intestinal epithelium of normal mice. The Ogt-VKO mice showed significantly lower non-fasted blood glucose levels and were underweight compared with litter matched controls. Glycaemic excursion in the Ogt-VKO mice was significantly lower during the oral glucose tolerance test but comparable during the intraperitoneal glucose tolerance test. Furthermore, the Ogt-VKO mice exhibited lower Sglt1 expression in the small intestine compared with the control mice. We obtained similar results using the Ogt-iVKO mice only after tamoxifen administration. The oral D-xylose administration test revealed that the intestinal sugar absorption was diminished in the Ogt-iVKO mice and that GLP-1 secretion did not sufficiently increase after glucose gavage in the Ogt-iVKO mice. When using STC-1 cells, O-GlcNAcylation increased Sglt1 mRNA via a PKA/CREB-dependent pathway.Conclusion: Collectively, loss of O-GlcNAcylation in the intestine reduced glucose absorption via suppression of SGLT1 expression; this may lead to new treatments for malabsorption, obesity and diabetes. (C)& nbsp;2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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